Project Abstract The overall goal of our research is to determine whether treatment of a Major Depressive Disorder (MDD) improves the outcomes of patients with chronic kidney disease (CKD). We showed that MDD is present in up to 25% of CKD patients and independently associated with progression of CKD to End-Stage Kidney Disease, hospitalization, and death. Depression was also shown to be associated with adverse patient-centered outcomes such as lower quality of life (QOL), fatigue, poor sleep, and non-adherence to diet and medications. However, evidence for efficacy and tolerability of commonly-used antidepressant medications or nonpharmacologic treatments are very limited in CKD patients. Previous data, primarily derived from dialysis-dependent patients, were limited by small samples, lack of randomization and control, short durations, and high dropout rates. Our group was the first to conduct a double-blind randomized controlled trial for MDD treatment in 201 patients with non-dialysis CKD, and showed that sertraline, a commonly used selective serotonin reuptake inhibitor (SSRI), was no more efficacious than placebo for improving depressive symptoms. Given the high prevalence of MDD in CKD, its association with adverse outcomes, and lack of data to support efficacy of conventional treatments, it becomes imperative to test novel strategies to treat MDD in CKD patients. We propose to compare with a control group, the efficacy and tolerability of two novel treatment strategies - (1) Behavioral Activation Teletherapy (BAT) for 16 weeks, with the addition of bupropion, a non-SSRI antidepressant, at 8 weeks for patients whose depression has not remitted (non-remitters); and (2) bupropion for 16 weeks, with the addition of BAT at 8 weeks for non-remitters. In Aim 1, we will investigate the efficacy and tolerability of these 2 strategies vs. control for improvement in a primary endpoint of depressive symptoms in 201 patients (67 per group) with non-dialysis CKD stages 3b-5 and MDD at 2 sites, randomized 1:1:1 to either strategy or a control group of Clinical Management plus placebo. We hypothesize that either approach vs. control will result in a minimal clinically important difference of 2 points improvement in depressive symptoms, as ascertained blindly by the Quick Inventory of Depressive Symptomatology. In Aim 2 we will investigate the efficacy and tolerability of 8 weeks of (1) single-blind BAT plus placebo or (2) double-blind bupropion plus Clinical Management vs. control for improvement in depressive symptoms. In Aim 3, we will compare the efficacy of these 2 treatments strategies vs. control for improvement in CKD patient-centered outcomes including a. adherence to medications and healthcare visits; b. fatigue; c. sleep; and d. overall functioning. A clinical trial is urgently needed to address the evidence gap that exists for MDD treatment in CKD patients. Establishing the efficacy of 2 different strategies would be imperative, so that if found to be comparably efficacious, the option most acceptable to patients could be offered in clinical practice. We have a track-record of successfully conducting multicenter trials in CKD and have assembled a team of highly qualified investigators at 2 sites to ensure successful project completion.